Title:Molecular
Mechanisms of Development and Reversal of Alcohol-Induced Liver Fibrosis (R21)

Announcement TypeNew

Update: The following update relating to this announcement has been issued:

December 18, 2009 -
This FOA has been updated to reflect the new requirements from NIH’s Enhancing Peer Review Initiative. The new requirements are effective for submissions intended for due dates January 25, 2010 and beyond. If submitting an application intended for a due date of January 25, 2010 and beyond, follow the guidance below and be sure to use the Adobe-Forms-B version of the application forms and instructions. If applying for a due date before January 25, 2010, follow the guidance in the archived version of this FOA and be sure to use the Adobe-Forms-A version of the application forms and instructions.

NOTICE: Applications submitted in response to this Funding
Opportunity Announcement (FOA) for Federal assistance must be submitted
electronically through Grants.gov (http://www.grants.gov)
using the SF424 Research and Related (R&R) forms and the SF424 (R&R)
Application Guide.

APPLICATIONS MAY NOT BE SUBMITTED IN PAPER FORMAT.

This FOA must be read in conjunction with the application
guidelines included with this announcement in Grants.gov/Apply for Grants (hereafter
called Grants.gov/Apply).

A registration process is necessary before submission and
applicants are highly encouraged to start the process at least four weeks prior
to the grant submission date. See Section IV.

Purpose.This Funding Opportunity Announcement (FOA) issued by National Institute on
Alcohol Abuse and Alcoholism, National Institutes of Health, solicits
Research Grant (R21) applications from institutions/organizations that
propose to investigate the underlying molecular mechanisms of the development as well as reversal of
alcohol-induced liver fibrosis. Liver fibrosis
comprises excessive deposition of extracellular matrix (ECM) components,
especially collagen, and activation of hepatic stellate cells (HSCs) is
the primary event that triggers the process of fibrogenesis. Understanding
the mechanisms of alcohol-induced liver fibrosis is important for the
development of strategies for prevention and treatment of this condition.
This FOA encourages applicants to test small molecules that reverse or
prevent alcohol-induced liver fibrosis.

Mechanism
of Support.This FOA will utilize the NIH Research
Project Grant (R21) award mechanismand runs in parallel with an FOA of identical
scientific scope, PA-07-360 that solicits applications under the R01 mechanism.

Funds Available and Anticipated Number of Awards. Because the nature and scope of the proposed research
will vary from application to application, it is anticipated that the size and
duration of each award will also vary. The total amount awarded and the number
of awards will depend upon the mechanism numbers, quality, duration, and costs
of the applications received.

Budget and Project Period: The total project period for an
application submitted in response to this funding opportunity may not exceed
two years. Direct costs are limited to $275,000 over an R21 two-year period,
with no more than $200,000 in direct costs allowed in any single year. The R21 is
not renewable.

Eligible
Project Directors/Principal Investigators (PDs/PIs): Individuals with the skills, knowledge, and
resources necessary to carry out the proposed research are invited to work
with their institution to develop an application for support. Individuals
from underrepresented racial and ethnic groups as well as individuals with
disabilities are always encouraged to apply for NIH support.

Application and Submission
Information:Applicants may submit more than one
application, provided each application is scientifically distinct.

Renewals and Resubmissions.The R21 is not renewable.Applicants may submit a resubmission, but such applications must include an Introduction addressing issues raised in the previous critique (Summary Statement).

Number of PDs/PIs. More than one
PD/PI, or multiple PDs/PIs, may be designated on the application.

The
National Institute on Alcohol Abuse and Alcoholism invites grant applications
that will employ an integrated approach to investigate the underlying molecular
mechanisms of the development as well as reversal of alcohol-induced liver
fibrosis. Liver fibrosis is characterized by excessive deposition of
extracellular matrix (ECM) components, especially collagen, due to increased
matrix production and/or decreased matrix degradation. Activation of hepatic
stellate cells (HSCs) is the primary event that triggers the process of
fibrogenesis. Understanding the underlying molecular mechanisms by which
chronic alcohol consumption leads to the development of liver fibrosis, and the
mechanisms by which liver fibrosis is reversed, is important for the development
of strategies for prevention and treatment of this condition.

A.
Development of Liver Fibrosis: Published studies have identified the following factors as contributors to
the development of alcohol-induced liver fibrosis.

A1.
Acetaldehyde:

Acetaldehyde,
an immediate metabolite of ethanol, is primarily produced in hepatocytes and
can diffuse out to activate HSCs in a paracrine manner. Acetaldehyde has been
shown to increase collagen production by cultured rat HSCs in vitro via:1)
increasing the transcription of a1(I)
collagen gene; 2) decreasing the synthesis of matrix metalloproteinases-1, an
enzyme known to degrade type I collagen; and 3) increasing the expression of
other extracellular matrix components, including type III collagen and fibronectin.
Acetaldehyde also up-regulates transforming growth factor beta1 (TGF-β1)
expression, suggesting that some fibrogenic actions of acetaldehyde could be
indirectly mediated by TGF- β1. Acetaldehyde increased cell
membrane-associated PKC activity of HSCs, whereas PKC inhibitors blocked
acetaldehyde-mediated a1(I) collagen gene up regulation,
suggesting a role of this kinase in transducing the intracellular signal.
However, subsequent steps involved in the signal transduction pathways are not
clear, and the molecular mechanisms whereby acetaldehyde up-regulates gene
transcription for collagen and other matrix proteins are not well understood.

A2.
Oxidative stress:

Chronic
alcohol ingestion causes oxidative stress in the liver by increasing generation
of superoxide anions, hydrogen peroxide, hydroxyl radicals and lipid
peroxidation products. It also decreases glutathione levels in the liver. These
ROS have been shown to stimulate HSC proliferation and collagen synthesis.
Lipid peroxidation products such as malondialdehyde (MDA), and 4-hydroxynonenal
(4-HNE) have been implicated in hepatic fibrosis due to chronic ethanol
administration. Furthermore, MDA and 4-HNE have been shown to induce gene
expression of procollagen a1(I) and
increase collagen production by several folds in cultured HSCs. Studies are
needed to clarify the role, if any, of lipid peroxidation products in
activating quiescent HSC, and identify the molecular and signal transduction
pathways involved in this process.

A3. Role of
Kupffer cells:

Kupffer
cells have been implicated as mediators of alcoholic liver injury through the
release of free radicals as well as generation of inflammatory and fibrogenic
mediators in response to alcohol and lipopolysaccharide (LPS). Tumor necrosis
factor-alpha (TNF-α) produced by activated Kupffer cells may contribute to
HSC activation by inducing apoptosis of hepatocytes. In addition, Kupffer
cell-derived TGF-β1has been implicated in the activation of stellate cells
through a paracrine mechanism. Furthermore, using co-cultures of Kupffer cells
and HSCs, it was demonstrated that the stimulatory effect of Kupffer cells on
HSC collagen I production was mediated through xanthine oxidase, NADPH oxidase,
and CYP2E1, which are known sources of ROS. These results suggest a role of
oxidative stress in Kupffer cell-mediated HSC activation. Further studies are
necessary to understand the relative contribution of Kupffer cell mediators and
how this information can be used to prevent fibrosis.

A4.
Lipopolysaccharide (LPS):

Chronic
ethanol exposure is associated with increased transfer of LPS (endotoxin) from
the intestine to portal vein. Elevated levels of endotoxin in plasma can
activate Kupffer cells leading to release of pro-inflammatory and
pro-fibrogenic cytokines and both of these factors can contribute to fibrosis.
Recently, researchers have discovered that activated human HSCs express
LPS-recognizing receptors such as CD14 and TLR4. Furthermore, LPS was shown to
induce activation of NF-kB and JNK and expression of chemokines and adhesion
molecules in activated human HSCs. In cultured rat HSCs, LPS induced expression
of TNF-α, iNOS, and IL-6, which was initiated by MAPK p38 and mediated by
NF-kB. These results suggest that in addition to playing an indirect role via
Kupffer cell activation, LPS may contribute to hepatic fibrosis directly by
regulating gene expression of inflammatory mediators in HSCs. How do these
inflammatory mediators activate HSCs and increase collagen production is not
clear.

A5. Role of
hepatocyte apoptosis:

Hepatocyte
apoptosis is significantly increased in patients with alcoholic hepatitis, and
correlates with disease severity and hepatic fibrosis. Increased apoptosis of
hepatocytes results in increased fibrosis in experimental models. Hepatocyte
apoptosis produces chemokines and inflammation, which in turn may activate
HSCs. Furthermore, apoptosis of hepatocytes results in generation of apoptotic
bodies which can release lipid signals for uptake by Kupffer cells and HSCs.
Phagocytosis of the apoptotic bodies by HSCs and Kupffer cells enhances their
expression of pro-fibrogenic genes, such as TGF-β1, that may initiate HSC
activation. These studies suggest that alcohol-induced apoptosis of hepatocytes
may be a mechanism of liver fibrosis. Further studies are required to clarify
the mechanisms by which alcohol ingestion induces the formation of apoptotic
bodies and how these bodies activate HSCs.

A6.
Transforming growth factor-beta1 (TGF-b1):

TGF-b1 is a potent profibrogenic cytokine involved in
hepatic fibrosis. In the liver, it is expressed in Kupffer cells, sinusoidal
endothelial cells and HSCs. It activates HSCs resulting in their conversion to
myofibroblasts which produce excess of ECM proteins including collagens. TGF-b1 can indirectly enhance collagen production via
increasing the expression of platelet-derived growth factor (PDGF), which is a
potent mitogen for HSC proliferation, and by up-regulating the expression of
connective tissue growth factor (CTGF), a fibrogenic cytokine. In addition,
TGF-b1 can enhance its own production in
HSCs in an autocrine manner. Thus, once TGF-b1
is secreted, it can perpetuate both HSC proliferation and increased matrix
production that can result in fibrosis. Recently researchers have discovered
the inhibitor of differentiation 1 (Id1) gene that appears to be a critical
mediator in the TGF-b1-induced transdifferentiation of
rat HSCs. The possible involvement of TGF-b1
in alcohol-induced liver fibrosis is based on the following information.
Patients with advanced alcoholic liver disease exhibit increased hepatic
expression of TGF-b1 mRNA as well as increased serum
levels of TGF-b1. In addition, Kupffer cells
isolated from chronically ethanol exposed rats secreted TGF-b1 which induced Collagen production in HSCs.
Furthermore, acetaldehyde has been shown to enhance the production of TGF-b1 in cultured HSCs. How to use the available
information on TGF-β1 for the treatment of liver fibrosis needs further
research.

A7.
Platlet-derived growth factor (PDGF):

PDGF is the
most potent mitogen for HSCs and is therefore likely to be an important
mediator of the increased proliferation of HSCs during hepatic fibrogenesis in
chronic liver diseases. Upregulation of the PDGF receptorb during the transition of quiescent stellate cell to
activated stellate cells is an early event following liver injury. PDGF
produced from activated HSCs, activated Kupffer cells, and infiltrating
macrophages can stimulate HSC proliferation through PDGF receptorb during liver fibrogenesis. TGF-b1, a fibrogenic cytokine, has been shown to
potentiate PDGF-stimulated cell proliferation via inducing expression of PDGF
receptorb. The role of PDGF in mediating the
fibrogenic effect of chronic ethanol in liver needs investigation.

A8.
Connective tissue growth factor (CTGF):

CTGF is a
profibrogenic molecule which is over-expressed in fibrotic liver. CTGF
expression in cultured HSCs is enhanced following their activation or
stimulation by TGF-b1 which itself is a fibrogenic
cytokine. Exogenous CTGF is capable of promoting adhesion and proliferation of
cultured HSCs as well as collagen production by these cells. In addition, CTGF
contributes to the survival of primary HSCs through activation of NF-kappaB
pathway. Furthermore, CTGF is produced at high levels in hepatocytes during
CYP2E1-mdiated ethanol metabolism. The CTGF produced in hepatocytes may
activate HSCs in a paracrine manner. Taken together, these findings suggest a
role of CTGF in alcohol-induced hepatic fibrosis; however, further research is
needed to establish this connection.

A9.
Adenosine:

Adenosine,
a potent endogenous regulator of inflammation and tissue repair, is released in
vitro by HepG2 cells in response to ethanol or methotrexate treatment.
Activation of adenosine A2A receptor promotes stellate cell collagen
production. Adenosine release was increased in the liver in response to carbon
tetrachloride (CCl4) and thioacetamide exposure and this was
associated with the development of liver fibrosis. However,

A2 A receptor deficient mice were protected from development of hepatic fibrosis
following exposure to CCl4 or thioacetamide. Whether adenosine plays
a significant role in mediating alcoholic liver fibrosis remains to be
determined.

A10.
Leptin:

Leptin
plays an important role in the development of hepatic fibrosis. It is present
in activated stellate cells but not in quiescent HSCs. Leptin has been shown to
increase α1 (I) collagen mRNA and type I collagen production in human
stellate cell line, LX-1, and up-regulate α2(I) collagen gene expression in
cultured rat HSCs. This effect of leptin can be mediated through up-regulation
of TGF-β1, enhancement of the TGFβ1 type II receptor, or increased
production of tissue inhibitor of metalloproteinase-1 (TIMP-1) in activated HSCs. The mechanism of
leptin-induced alcoholic hepatic fibrosis is not clear.

A11. Role
of innate immunity :

The liver
immune system has predominant innate immunity (nonspecific immunity)
comprised of Kupffer cells, natural killer (NK) cells and NKT cells, and interferon
alpha (IFN-α) and interferon gamma (IFN-γ) cytokines. Increasing
evidence suggests that these innate immune cells and cytokines play important
roles in regulating the development and progression of liver fibrosis: a)
macrophages have been shown to inhibit liver fibrosis through killing HSCs and
enhancing matrix degradation during recovery; b) innate cytokines IFN-α
and IFN-γ inhibit liver fibrosis by blocking TGF-β1 signaling and HSC
activation; c) IFN-α in combination with ribavirin has been shown to
attenuate liver fibrosis in patients infected with hepatitis C virus (HCV); and
d) NK cells have been shown to kill activated HSCs
and attenuate the severity of liver fibrosis. These results suggest that
innate immunity (NK/IFNs) plays an important role in suppression of liver
fibrosis. Activation of the innate immune system (NK/IFNs) during HCV infection
may help to control the progression of hepatic fibrosis.

Alcohol-mediated
suppression of the innate immunity has been reported in both animal experiments
and clinical studies. Chronic alcohol consumption has been shown to decrease NK
cell activity and numbers. Decreased NK activity has also been reported in
human alcoholics. Acute ethanol exposure markedly suppresses IFN-b and IFN-g activation of STAT1 signaling pathways in primary hepatocytes. STAT2 and
protein kinase R, which are the key downstream signaling components for IFN-a, are significantly downregulated in human alcoholic
liver disease. Chronic alcohol consumption interferes with the efficacy of IFN-a treatment in HCV patients. Since these innate immune
cells and cytokines play an important role in suppressing liver fibrosis as
discussed above, alcohol suppression of innate immunity may be a mechanism
whereby alcohol accelerates liver fibrosis in HCV patients. Further research is
required to investigate the role of innate immune system in alcoholic liver
fibrosis.

A12. HCV
and liver fibrosis:

Alcohol
consumption is known to accelerate the process of liver fibrosis in patients
infected with HCV, but the mechanisms of this interaction are not clear.
Alcohol consumption has been shown to increase apoptosis of hepatocytes and
oxidative stress in patients with chronic hepatitis C virus infection.
Furthermore, HCV core protein and chronic alcohol consumption additively
increased lipid peroxidation and synergistically increased hepatic TNF-α
and TGF-β1 expression in HCV core protein-expressing transgenic mice. All these fibrogenic factors
apoptosis, oxidative stress, lipid peroxidation, TNF-α, and TGF-β1 -
may be involved in promoting the effect of alcohol on hepatic fibrosis in HCV
infected patients. Further research is required to establish the connection
between alcohol, HCV, and liver fibrosis and identify targets for intervention.

B.
Reversion of Liver Fibrosis

Reversion
of fibrosis may be accomplished by inducing apoptosis or necrosis of activated
HSCs, or by transformation of activated HSCs to quiescent phenotype.

B1. Apoptosis
of activated HSCs:

Spontaneous
resolution of experimental fibrosis is associated with the clearance of collagen-producing
α-SMA positive myofibroblasts (activated HSCs and transdifferentiated
portal fibroblasts), which has been attributed to the induction of apoptosis of
these cells. Apoptosis of myofibroblasts is associated with decreased
expression of TIMP mRNA but increased collagenase activity in the liver. This
concept of spontaneous reversion of fibrosis mediated by HSC apoptosis has been
used to design chemical-induced apoptosis of activated HSCs. For example,
gliotoxin induces apoptosis of activated HSC which resulted in the resolution
of liver fibrosis induced by CCl4 in experimental animals . In addition, sulfasalazine has
been shown to induce apoptosis of activated rat and human stellate cells in
vitro, and promote accelerated recovery from CCl4 -induced fibrosis
in rats. This effect was mediated through the inhibition of the inhibitor of
kappaB kinases, blocking the NF-kB pathway. TIMP-1 protects activated HSCs from
apoptosis and blocking TIMP-1 with specific monoclonal antibody reverses CCl4-induced
hepatic fibrosis. Hepatocyte growth factor (HGF)
stimulates hepatocyte regeneration but apoptosis of activated HSCs and reversal
of fibrosis. Further research is required to identify agents that will
selectively cause apoptosis of activated HSCs without adversely affecting
hepatocytes.

B2.
Necrosis of activated HSCs:

Activated
HSCs can be selectively killed by the endogenous cannabinoid anandamide via
inducing necrosis. Anandamide blocks HSC proliferation at concentrations of 1
to 10 micromol/L. At higher concentrations (25-100 micromol/L), anandamide
dose-dependently induced cell death in culture-activated and in vivo-activated
HSCs. The cell death was caspase-independent and showed typical features of
necrosis, such as rapid adenosine triphosphate depletion and propidium iodide
uptake. Anandamide induces ROS formation and increased intracellular Ca(2+)
levels. Pretreatment with the antioxidant glutathione or Ca(2+)-chelation
attenuated anandamide-induced cell death. In primary hepatocytes, anandamide
failed to induce cell death even after prolonged treatment. Thus, anandamide
efficiently induces necrosis in activated HSCs, an effect that depends on
membrane cholesterol and a subsequent increase in intracellular Ca(2+) and ROS.
The anti-proliferative effects and the selective killing of HSCs, but not
hepatocytes, indicate that anandamide may be used as a potential
anti-fibrogenic tool. Studies are required to test the efficacy and safety of
anandamide and other related agents in animal models of liver fibrosis.

One
theoretical approach to reverse fibrosis is the reverse trans-differentiation of
activated HSCs to quiescent phenotype. Quiescent HSCs are full of Vitamin A and
triglycerides which are depleted in the activated HSCs. The
adipogenic/lipogenic transcriptional regulation conferred by PPARγ,
LXRα, and SREBP-1c is required for the maintenance of the fat-storing
quiescence phenotype of HSCs. Expression of these adipogenic transcription
factors is lost in activated HSCs. On the other hand, treatment of the
activated HSCs with an adipocyte differentiation cocktail or ectopic expression
of PPARγ or SREBP-1c causes their reversal to the quiescent phenotype. Of
the known adipogenic transcription factors, PPARγ has been investigated
extensively. The expression of PPARγ is reduced in activated HSCs which
can be restored with PPARγ ligands. Furthermore, by using adenoviral
vector to ectopically express PPARγ in culture-activated HSCs, researchers
have demonstrated that expression of PPARγ can restore the morphological
and biochemical characteristics of quiescent HSCs, including accumulation of
vitamin A. These findings suggest a possibility that PPARγ and other
adipogenic factors may serve as important therapeutic targets for liver fibrosis.
Indeed, researchers have demonstrated the therapeutic efficacy of two
thiazolidinedione (TZD) derivatives, the PPARγ ligands pioglitazone and
rosiglitazone in two toxic and one cholestatic models of liver fibrosis.
However, in a recent human study, pioglitazone was found to be ineffective in
reducing liver fibrosis in subjects with nonalcoholic steatohepatitis. Further
studies are required to test the efficacy of PPARγ and other adipogenic
factors in the treatment of liver fibrosis.

Areas of Research:

Examples of
research that might be supported under this PA include, but are not limited to,
the following:

Understanding
the role of hepatocyte growth factor/scatter factor in the resolution of
hepatic fibrosis

Understanding
of the biology of matrix resorption

Elucidation
of the role of epigenetic factors in the development and reversal of liver
fibrosis

Evaluating the role of
cannabinoid receptor agonists and antagonists in the suppression of liver
fibrosis

The evolution and vitality of the biomedical sciences
require a constant infusion of new ideas, techniques, and points of view.
These may differ substantially from current thinking or practice and may not
yet be supported by substantial preliminary
data. By using the R21 mechanism, the NIH seeks to foster the
introduction of novel scientific ideas, model systems, tools, agents, targets,
and technologies that have the potential to substantially advance biomedical research.

The
R21 mechanism is intended to encourage new exploratory and developmental
research projects. For example, such projects could assess the
feasibility of a novel area of investigation or a new experimental system that
has the potential to enhance health-related
research. Another example could include the unique and innovative use of
an existing methodology to explore a new scientific area. These
studies may involve considerable risk but may lead to a breakthrough in a particular
area, or to the development of novel techniques,
agents, methodologies, models, or applications that could have a major impact
on a field of biomedical, behavioral, or clinical research.

Applications
for R21 awards should describe projects distinct from those supported through the traditional R01 mechanism. For
example, long-term projects, or projects designed to increase knowledge in a
well-established area, will not be considered for R21 awards.
Applications submitted under this mechanism should be exploratory and novel. These studies should break new ground or
extend previous discoveries toward new directions or applications.
Projects of limited cost or scope that use widely accepted approaches and
methods within well established fields are better suited for the R03 small grant mechanism. Information on the R03
program can be found at http://grants.nih.gov/grants/funding/r03.htm.

This FOA will use the NIH
Exploratory/Developmental Research Grant (R21) award
mechanism. As an applicant, you will be solely
responsible for planning, directing, and executing the proposed project.

This FOA uses Just-in-Time information concepts. It also uses the modular as
well as the non-modular budget formats (see the Modular Applications and
Awards section of the NIH
Grants Policy Statement. Specifically, if you are submitting an
application with direct costs in each year of $250,000 or less (excluding
consortium Facilities and Administrative [F&A] costs), use the PHS398
Modular Budget component provided in the SF424 (R&R) Application Package
and SF424 (R&R) Application Guide (see specifically Section 3.4, Modular
Budget Component, of the Application Guide).

All foreign applicants must complete and submit budget requests using
the Research & Related Budget component found in the application package
for this FOA. See NOT-OD-06-096,
August 23, 2006.

Exploratory/developmental grant support is for new
projects only; competing renewal (formerly competing continuation)
applications will not be accepted. Applicants may submit a resubmission, but such application must include
an Introduction addressing issues raised in the previous critique (Summary
Statement).

2. Funds Available

Because the nature and scope of the proposed research will vary from
application to application, it is anticipated that the size and duration of
each award will also vary. Although the financial plans of the Institutes and
Centers (ICs) provide support for this program, awards pursuant to this funding
opportunity are contingent upon the availability of funds and the submission of
a sufficient number of meritorious applications.

The
total project period for an application submitted in response to this funding
opportunity may not exceed 2 years. Although the size of award may vary with
the scope of research proposed, it is expected that
applications will stay within the budgetary guidelines for an
exploratory/developmental project; direct costs are limited to $275,000 over an
R21 two-year period, with no more than $200,000 in direct costs allowed in any single year. Applicants may request direct
costs in $25,000 modules, up to the total direct costs limitation of $275,000
for the combined two-year award period. NIH grants policies as described in the NOT-OD-05-004, November 2, 2004.

Section
III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

You may submit an
application(s) if your institution/organization has any of the following
characteristics:

Any individual with the skills,
knowledge, and resources necessary to carry out the proposed research as the
Project Director/Principal Investigator (PD/PI) is invited to work with his/her
organization to develop an application for support. Individuals from
underrepresented racial and ethnic groups as well as individuals with
disabilities are always encouraged to apply for NIH support.

More than one PD/PI, or
multiple PDs/PIs, may be designated on the application for projects that
require a team science approach that clearly does not fit the single-PD/PI
model. Additional information on the implementation plans and policies and
procedures to formally allow more than one PD/PI on individual research
projects is available at http://grants.nih.gov/grants/multi_pi.
All PDs/PIs must be registered in the NIH eRA Commons prior to the submission
of the application (see http://era.nih.gov/ElectronicReceipt/preparing.htm
for instructions).

The decision of whether to apply for a single PD/PI or
multiple PD/PI grant is the responsibility of the investigators and applicant
organizations and should be determined by the scientific goals of the project.
Applications for multiple PD/PI grants will require additional information, as
outlined in the instructions below. When considering multiple
PDs/PIs, please be aware that the structure and governance of the PD/PI
leadership team as well as the knowledge, skills and experience of the
individual PD/PIs will be factored into the assessment of the overall
scientific merit of the application. Multiple PDs/PIs on a project share the
authority and responsibility for leading and directing the project,
intellectually and logistically. Each PD/PI is responsible and accountable to
the grantee organization, or, as appropriate, to a collaborating organization,
for the proper conduct of the project or program, including the submission of
required reports. For further information on multiple PDs/PIs, please see http://grants.nih.gov/grants/multi_pi.

Applicants may submit more than one
application, provided each application is scientifically distinct.

Section IV. Application and Submission Information

To download a SF424 (R&R) Application Package and
SF424 (R&R) Application Guide for completing the SF424 (R&R) forms for
this FOA, link to http://www.grants.gov/Apply/ and follow the directions provided on that Web site.

A one-time registration is required for institutions/organizations at both:

The individual designated as the PD/PI on the application must
also be registered in the NIH eRA Commons. In the case of multiple PDs/PIs, all
PDs/PIs must be registered and be assigned the PI role in the eRA Commons prior to the submission of the application.

Each PD/PI must hold a PD/PI account in the Commons. Applicants should not share a Commons account for both an Authorized Organization
Representative/Signing Official (AOR/SO) role and a PD/PI role; however, if
they have both a PD/PI role and an Internet Assisted Review (IAR) role, both
roles should exist under one Commons account.

When multiple PDs/PIs are proposed, all PDs/PIs at the applicant
organization must be affiliated with that organization. PDs/PIs located at
another institution need not be affiliated with the applicant organization, but
must be affiliated with their own organization to be able to access the Commons. This registration/affiliation must be done by the AOR/SO or their designee who is
already registered in the Commons.

Both the PD/PI
and AOR/SO need separate accounts in the NIH eRA Commons since both are authorized
to view the application image.

Note that if a PD/PI is also an NIH peer-reviewer with an
Individual DUNS and CCR registration, that particular DUNS number and CCR
registration are for the individual reviewer only. These are different than any
DUNS number and CCR registration used by an applicant organization. Individual
DUNS and CCR registration should be used only for the purposes of personal
reimbursement and should not be used on any grant applications submitted to the
Federal Government.

Several of the steps of the registration process could
take four weeks or more. Therefore, applicants should immediately check with
their business official to determine whether their organization/institution is
already registered in both Grants.gov and
the Commons. The NIH will accept
electronic applications only from organizations that have completed all
necessary registrations.

1. Request Application Information

Applicants must download the SF424 (R&R)
application forms and SF424 (R&R) Application Guide for this FOA through Grants.gov/Apply.

Note: Only the forms package
directly attached to a specific FOA can be used. You will not be able to use
any other SF424 (R&R) forms (e.g., sample forms, forms from another FOA),
although some of the "Attachment" files may be useable for more than
one FOA.

Prepare all applications using the SF424 (R&R)
application forms and in accordance with the SF424
(R&R) Application Guide (MS
Word or PDF).

The SF424 (R&R) Application Guide is
critical to submitting a complete and accurate application to NIH. There are
fields within the SF424 (R&R) application components that, although not
marked as mandatory, are required by NIH (e.g., the Credential log-in field
of the Research & Related Senior/Key Person Profile component must
contain the PD/PIs assigned eRA Commons User ID). Agency-specific instructions
for such fields are clearly identified in the Application Guide. For additional
information, see Frequently Asked Questions Application Guide,Electronic Submission
of Grant Applications.

The SF424 (R&R) application is comprised of data
arranged in separate components. Some components are required, others are
optional. The forms package associated with this FOA in Grants.gov/APPLYwill include all
applicable components, required and optional. A completed application in
response to this FOA will include the following components:

Prepare detailed budgets for all applications
(that is, complete the Research & Related Budget component of the
SF424 (R&R) application forms not the PHS398 Modular Budget
component). See NOT-OD-06-096.

Charge
back of customs and import fees is not allowed.

Format:
Every effort should be made to comply with the format specifications,
which are based upon a standard U.S. paper size of 8.5 x 11 within each
PDF.

Funds
for up to 8% administrative costs (excluding equipment) may be requested.
See NOT-OD-01-028,
March 29, 2001.

Organizations
must comply with Federal/NIH policies on human subjects, animals, and
biohazards.

Organizations
must comply with Federal/NIH biosafety and biosecurity regulations. See Section VI.2., Administrative and National Policy
Requirements.

Proposed
research should provide special opportunities for furthering research programs
through the use of unusual talent, resources, populations, or environmental
conditions in other countries that are not readily available in the United States or that augment existing U.S. resources.

SPECIAL INSTRUCTIONS

Applications with Multiple PDs/PIs

When
multiple PDs/PIs are proposed, NIH requires one PD/PI to be designated as the
"Contact PI, who will be responsible for all communication between the
PDs/PIs and the NIH, for assembling the application materials outlined below,
and for coordinating progress reports for the project. The contact PD/PI must
meet all eligibility requirements for PD/PI status in the same way as other
PDs/PIs, but has no other special roles or responsibilities within the project
team beyond those mentioned above.

Information
for the Contact PD/PI should be entered in Item 13 of the SF424(R&R) Cover
component. All other PDs/PIs should be listed in the Research &
Related Senior/Key Person component and assigned the project role of
PD/PI. Please remember that all PDs/PIs must be registered in the eRA
Commons prior to application submission. The Commons ID of each PD/PI
must be included in the Credential field of the Research & Related
Senior/Key Person component. Failure to include this data field will cause
the application to be rejected.

All projects proposing Multiple PDs/PIs will be
required to include a new section describing the leadership of the project.

Multiple
PD/PI Leadership Plan: For applications designating multiple PDs/PIs, a new
section of the research plan, entitled Multiple PD/PI Leadership Plan, must be included. A rationale for
choosing a multiple PD/PI approach should be described. The governance and
organizational structure of the leadership team and the research project should
be described, including communication plans, process for making decisions on
scientific direction, and procedures for resolving conflicts. The roles
and administrative, technical, and scientific responsibilities for the project
or program should be delineated for the PDs/PIs and other collaborators.

If budget allocation is
planned, the distribution of resources to specific components of the project or
the individual PDs/PIs should be delineated in the Leadership Plan. In the
event of an award, the requested allocations may be reflected in a footnote on
the Notice of Award.

Applications Involving a Single Institution

When
all PDs/PIs are within a single institution, follow the instructions contained
in the SF424 (R&R) Application Guide.

Applications Involving Multiple Institutions

When
multiple institutions are involved, one institution must be designated as the
prime institution and funding for the other institution(s) must be requested
via a subcontract to be administered by the prime institution. When submitting
a detailed budget, the prime institution should submit its budget using the
Research & Related Budget component. All other institutions should
have their individual budgets attached separately to the Research & Related
Subaward Budget Attachment(s) Form. See Section 4.8 of the SF424 (R&R)
Application Guide for further instruction regarding the use of the subaward budget
form.

When
submitting a modular budget, the prime institution completes the PHS398 Modular
Budget component only. Information concerning the consortium/subcontract
budget is provided in the budget justification. Separate budgets for each
consortium/subcontract grantee are not required when using the Modular budget
format. See Section 3.4 of the Application Guide for further instruction
regarding the use of the PHS398 Modular Budget component.

To submit an application in response to this FOA, applicants should access this
FOA via http://www.grants.gov/Apply and follow steps 1-4. Note: Applications must only be submitted
electronically. PAPER APPLICATIONS WILL NOT BE ACCEPTED. 3.C. Application
Processing

Applications may be submitted on or after
the opening date and must be successfully received by Grants.gov no
later than 5:00 p.m. local time (of the
applicant institution/organization) on the
application submission/receipt date(s). (See Section IV.3.A. for all dates.) If an application is not submitted by the receipt
date(s) and time, the application may be delayed in the review process or not
reviewed.

Once an application package has been successfully
submitted through Grants.gov, any errors have been addressed, and the assembled
application has been created in the eRA Commons, the PD/PI and the Authorized
Organization Representative/Signing Official (AOR/SO) have two business days to
view the application image.

If everything is acceptable, no
further action is necessary. The application will automatically move forward
for processing by the Division of Receipt and Referral, Center for Scientific
Review, NIH, after two business days.

Prior to the submission deadline,
the AOR/SO can Reject the assembled application and submit a
changed/corrected application within the two day viewing window. This option
should be used if the AOR/SO determines that warnings should be addressed.
Reminder: warnings do not stop further application processing. If an
application submission results in warnings (but no errors) it will
automatically move forward after two business days if no action is taken.
Please remember that some warnings may not be applicable or may need to be
addressed after application submission.

If the two day window falls after
the submission deadline, the AOR/SO will have the option to Reject the
application if, due to an eRA Commons or Grants.gov system issue, the
application does not correctly reflect the submitted application package (e.g.,
some part of the application was lost or did not transfer correctly during the
submission process). The AOR/SO should first contact the eRA Commons Helpdesk to confirm the
system error, document the issue, and determine the best course of action. NIH
will not penalize the applicant for an eRA Commons or Grants.gov system issue.

If the AOR/SO chooses to Reject
the image after the submission deadline for a reason other than an eRA Commons or Grants.gov system failure, a changed/corrected application still can be
submitted but it will be subject to the NIH late
policy guidelines and may not be accepted. The reason for this delay should
be explained in the cover letter attachment.

Both the AOR/SO and PD/PI will
receive e-mail notifications when the application is rejected or the
application automatically moves forward in the process after two days.

Upon receipt, applications will
be evaluated for completeness by the Center for Scientific Review, NIH.
Incomplete applications will not be reviewed.

There will be an acknowledgement of receipt of
applications from Grants.gov and the Commons. Information related to the
assignment of an application to a Scientific Review Group is also in the Commons.

Note: Since email can be unreliable, it is the
responsibility of the applicant to check periodically on their application
status in the Commons.

The NIH will not accept any
application in response to this FOA that is essentially the same as one
currently pending initial merit review unless the applicant withdraws the
pending application. The NIH will not accept any application that is
essentially the same as one already reviewed. This does not preclude the
submission of an application already reviewed with substantial changes, but
such application must include an Introduction addressing the previous
critique. Note such an application is considered a "resubmission" for
the SF424 (R&R).

All NIH awards are subject to the terms and
conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable. A
grantee may, at its own risk and without NIH prior approval, incur obligations
and expenditures to cover costs up to 90 days before the beginning date of the
initial budget period of a new award if such costs: are necessary to conduct
the project, and would be allowable under the grant, if awarded, without NIH
prior approval. If specific expenditures would otherwise require prior approval,
the grantee must obtain NIH approval before incurring the cost. NIH prior
approval is required for any costs to be incurred more than 90 days before the
beginning date of the initial budget period of a new award.

The incurrence of pre-award costs in anticipation of a
competing or non-competing award imposes no obligation on NIH either to make
the award or to increase the amount of the approved budget if an award is made
for less than the amount anticipated and is inadequate to cover the pre-award
costs incurred. NIH expects the grantee to be fully aware that pre-award costs
result in borrowing against future support and that such borrowing must not
impair the grantee's ability to accomplish the project objectives in the
approved time frame or in any way adversely affect the conduct of the project.
See the NIH
Grants Policy Statement.

6. Other Submission
Requirements

PD/PI
Credential (e.g., Agency Login)

The NIH requires the PD/PI to
fill in his/her Commons User ID in the PROFILE Project Director/Principal
Investigator section, Credential log-in field of the Research & Related
Senior/Key Person Profile component. The applicant organization must include
its DUNS number in its Organization Profile in the eRA Commons. This DUNS
number must match the DUNS number provided at CCR registration with Grants.gov.
For additional information, see Registration FAQs Important Tips -- Electronic Submission
of Grant Applications.

Organizational DUNS

The applicant organization must
include its DUNS number in its Organization Profile in the eRA Commons. This DUNS number must match the DUNS number provided at CCR registration with
Grants.gov. For additional information, see Frequently Asked Questions
Application Guide, Electronic
Submission of Grant Applications.

PHS398 Research Plan Component Sections

While each section of the Research Plan needs to be uploaded separately as a PDF attachment, applicants
are encouraged to construct the Research Plan component as a single document,
separating sections into distinct PDF attachments just before uploading the
files. This approach will enable applicants to better monitor formatting
requirements such as page limits. All attachments must be provided to NIH in
PDF format, filenames must be included with no spaces or special characters,
and a .pdf extension must be used.

All application instructions outlined in the SF424
(R&R) Application Guide (MS
Word or PDF) are to be followed, incorporating "Just-in-Time" information
concepts, and with the following requirements for R21 applications:

R21 applications will use the
modular budget format and "Just-in-Time" information concepts, with
direct costs requested in $25,000 modules, up to the total direct costs
limitation of $275,000 over an R21 two-year period. No more than $200,000 in
direct costs will be allowed in any single year.

Item 3 of the Research Plan of the R21
application may not exceed 6 pages, including tables, graphs,
figures, diagrams, and charts.

Introduction (required for a
resubmission application) is limited to one page.

Do not use the Appendix to circumvent the page limitations. An application that does not observe these limitations may be
delayed in the review process.

Note: While each section of
the PHS398 Research Plan component needs to be uploaded separately as a PDF
attachment, applicants are encouraged to construct the Research Plan component
as a single document, separating sections into distinct PDF attachments just
before uploading the files. This approach will enable applicants to monitor
better formatting requirements such as page limits. All attachments must be
provided to NIH in PDF format, filenames must be included with no spaces or
special characters, and a .pdf extension must be used.

Foreign Applications (Non-domestic
(non-U.S.) Entity)

Indicate how the
proposed project has specific relevance to the mission and objectives of the IC
and has the potential for significantly advancing the health sciences in the United States.

Plan for Sharing Research Data

The precise content of the data-sharing plan will
vary, depending on the data being collected and how the investigator is
planning to share the data. Applicants who are planning to share data may wish
to describe briefly the expected schedule for data sharing, the format of the
final dataset, the documentation to be provided, whether or not any analytic
tools also will be provided, whether or not a data-sharing agreement will be
required and, if so, a brief description of such an agreement (including the
criteria for deciding who can receive the data and whether or not any
conditions will be placed on their use), and the mode of data sharing (e.g.,
under their own auspices by mailing a disk or posting data on their
institutional or personal website, through a data archive or enclave).
Investigators choosing to share under their own auspices may wish to enter into
a data-sharing agreement. References to data sharing may also be appropriate in
other sections of the application.

All applicants must include a plan for sharing research data in their
application. The data sharing policy is available at http://grants.nih.gov/grants/policy/data_sharing.
All investigators responding to this funding opportunity should include a
description of how final research data will be shared, or explain why data
sharing is not possible.

The reasonableness of the data sharing plan or the rationale for not sharing
research data will be assessed by the reviewers. However, reviewers will not
factor the proposed data sharing plan into the determination of scientific
merit or the impact/priority score.

Sharing Research Resources

NIH
policy expects that grant recipients make unique research resources readily
available for research purposes to qualified individuals within the scientific
community after publication (See the NIH Grants Policy Statementhttp://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm#_Toc54600131).
Investigators responding to this funding opportunity should include a sharing
research resources plan addressing how unique research resources will be shared
or explain why sharing is not possible.

The adequacy of the resources sharing plan and any
related data sharing plans will be considered by Program staff of the funding
organization when making recommendations about funding applications. The
effectiveness of the resource sharing will be evaluated as part of the
administrative review of each Non-Competing Grant
Progress Report (PHS 2590). See Section VI.3.,
Reporting.

Section
V. Application Review Information

1. Criteria (Update: Enhanced review criteria have been issued for the evaluation of research applications received for potential FY2010 funding and thereafter - see NOT-OD-09-025).

Only the review criteria described below will be
considered in the review process.

2. Review and
Selection Process

Applications submitted for this funding
opportunity will be assigned to the ICs on the basis of established Public Health Service (PHS) referral
guidelines.

Undergo a
selection process in which only those applications deemed to have the
highest scientific merit, generally the top half of applications under
review, will be discussed and assigned an impact/priority score.

Receive a
written critique.

Receive a second level of review by an
appropriate advisory council or board

Applications submitted in
response to this funding opportunity will compete for available funds with all
other recommended applications. The following will be considered in making
funding decisions:

Scientific
merit of the proposed project as determined by peer review.

Availability
of funds.

Relevance
to program priorities.

The NIH R21 exploratory/developmental grant is a
mechanism for supporting novel scientific ideas or new model systems, tools,
or technologies that have the potential to significantly advance our
knowledge or the status of health-related research. Because the
Research Plan component is limited to 6 pages, an exploratory/developmental grant application need not
have extensive background material or preliminary information as one might
normally expect in an R01 application. Accordingly, reviewers will focus
their evaluation on the conceptual framework, the level of innovation, and the
potential to significantly advance our knowledge or understanding.
Reviewers will place less emphasis on methodological details and certain
indicators traditionally used in evaluating the scientific merit of R01
applications, including supportive preliminary data. Appropriate justification
for the proposed work can be provided through literature citations, data from
other sources, or, when available, from investigator-generated data.
Preliminary data are not required for R21 applications; however, they may be
included if available.

The goals of NIH supported
research are to advance our understanding of biological systems, to improve the
control of disease, and to enhance health. In their written critiques,
reviewers will be asked to comment on each of the following criteria in order
to judge the likelihood that the proposed research will have a substantial
impact on the pursuit of these goals. Each of these criteria will be addressed
and considered in assigning the overall score, weighting them as appropriate
for each application.

Significance

Investigator

Innovation

Approach

Environment

Note that an application does not
need to be strong in all categories to be judged likely to have major
scientific impact and thus deserve a high impact/priority score. For example, an
investigator may propose to carry out important work that by its nature is not
innovative but is essential to move a field forward.

Overall Impact. Reviewers will provide an overall impact/priority score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following five core review criteria, and additional review criteria (as applicable for the project proposed).

Core Review Criteria. Reviewers will consider each of the five review criteria below in the determination of scientific and technical merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance: Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Investigator(s): Are the PD/PIs, collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Innovation: Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Approach: Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?
If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

Environment: Does the
scientific environment in which the work will be done contribute to the
probability of success? Do the proposed studies benefit from unique features of
the scientific environment, or subject populations, or employ useful
collaborative arrangements? Is there evidence of institutional support?

Additional Review Criteria

As applicable for the project
proposed, reviewers will consider the following additional items in the
determination of scientific and technical merit, but will not give separate
scores for these items.

Protections for Human Subjects. For
research that involves human subjects but does not involve one of the six
categories of research that are exempt under 45 CFR Part 46, the committee will
evaluate the justification for involvement of human subjects and the proposed
protections from research risk relating to their participation according to the
following five review criteria: 1) risk to subjects, 2) adequacy of protection
against risks, 3) potential benefits to the subjects and others, 4) importance
of the knowledge to be gained, and 5) data and safety monitoring for clinical
trials.

For research that involves human subjects and meets
the criteria for one or more of the six categories of research that are exempt
under 45 CFR Part 46, the committee will evaluate: 1) the justification for the
exemption, 2) human subjects involvement and characteristics, and 3) sources of
materials.

Inclusion of Women, Minorities, and Children.
When the proposed project involves clinical research, the committee will
evaluate the proposed plans for inclusion of minorities and members of both
genders, as well as the inclusion of children.

Vertebrate Animals. The committee
will evaluate the involvement of live vertebrate animals as part of the
scientific assessment according to the following five points: 1) proposed use of
the animals, and species, strains, ages, sex, and numbers to be used; 2)
justifications for the use of animals and for the appropriateness of the species
and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting
discomfort, distress, pain and injury to that which is unavoidable in the
conduct of scientifically sound research including the use of analgesic,
anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and
5) methods of euthanasia and reason for selection if not consistent with the
AVMA Guidelines on Euthanasia.

Resubmission Applications. When
reviewing a Resubmission application (formerly called an amended application),
the committee will evaluate the application as now presented, taking into
consideration the responses to comments from the previous scientific review
group and changes made to the project.

Renewal Applications. When reviewing
a Renewal application (formerly called a competing continuation application),
the committee will consider the progress made in the last funding period.

Revision Applications. When
reviewing a Revision application (formerly called a competing supplement
application), the committee will consider the appropriateness of the proposed
expansion of the scope of the project. If the Revision application relates to a
specific line of investigation presented in the original application that was
not recommended for approval by the committee, then the committee will consider
whether the responses to comments from the previous scientific review group are
adequate and whether substantial changes are clearly evident.

Biohazards. Reviewers will assess
whether materials or procedures proposed are potentially hazardous to research
personnel and/or the environment, and if needed, determine whether adequate
protection is proposed.

Additional Review Considerations

As applicable for the
project proposed, reviewers will address each of the following items, but will
not give scores for these items and should not consider them in providing an
overall impact score.

Budget and Period Support. Reviewers
will consider whether the budget and the requested period of support are fully
justified and reasonable in relation to the proposed research.

Select Agents Research. Reviewers
will assess the information provided in this section of the application,
including 1) the Select Agent(s) to be used in the proposed research, 2) the
registration status of all entities where Select Agent(s) will be used, 3) the
procedures that will be used to monitor possession use and transfer of Select
Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security
of the Select Agent(s).

Applications from Foreign Organizations.
Reviewers will assess whether the project presents special opportunities for
furthering research programs through the use of unusual talent, resources,
populations, or environmental conditions that exist in other countries and
either are not readily available in the United States or augment existing U.S.
resources.

Data Sharing Plan: The reasonableness of the
data sharing plan or the rationale for not sharing research data will be
assessed by the reviewers. However, reviewers will not factor the proposed data
sharing plan into the determination of scientific merit or the impact/priority score.
The presence of a data sharing plan will be part of the terms and conditions of
the award. The funding organization will be responsible for monitoring the data
sharing policy.

2.D. Sharing Research
Resources

NIH policy expects
that grant recipients make unique research resources readily available for
research purposes to qualified individuals within the scientific community
after publication (See the NIH Grants Policy Statementhttp://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm#_Toc54600131).
Investigators responding to this funding opportunity should include a sharing
research resources plan addressing how unique research resources will be shared
or explain why sharing is not possible.

Program staff will be responsible for the
administrative review of the plan for sharing research resources.

The adequacy of the resources
sharing plan and any related data sharing plans will be considered by Program
staff of the funding organization when making recommendations about funding
applications. The effectiveness of the resource sharing will be evaluated as
part of the administrative review of each Non-Competing Grant
Progress Report (PHS 2590), See Section VI.3.,
Reporting.Model Organism Sharing Plan: Reviewersare asked to assess the sharing
plan in an administrative note. The sharing plan itself should be discussed
after the application is scored. Whether a sharing plan is reasonable can be
determined by the reviewers on a case-by-case basis, taking into consideration
the organism, the timeline, the applicant's decision to distribute the resource
or deposit it in a repository, and other relevant considerations. For the R21
mechanism, the presence or adequacy of a plan should not enter into the scoring
of the application.

3.
Anticipated Announcement and Award Dates

Not Applicable.

Section
VI. Award Administration Information

1.
Award Notices

After the peer review of the application is completed, the PD/PI will be able
to access his/her Summary Statement (written critique) via the NIH eRA Commons.

A formal notification in the form of a Notice of Award
(NoA) will be provided to the applicant organization. The NoA signed by the grants
management officer is the authorizing document. Once all administrative and
programmatic issues have been resolved, the NoA will be generated via email
notification from the awarding component to the grantee business official.

Selection of an application for award is not an
authorization to begin performance. Any costs incurred before receipt of the
NoA are at the recipient's risk. These costs may be reimbursed only to the
extent considered allowable pre-award costs. See Section
IV.5., Funding Restrictions.

We encourage your inquiries
concerning this funding opportunity and welcome the opportunity to answer
questions from potential applicants. Inquiries may fall into three areas:
scientific/research, peer review, and financial or grants management issues:

Human Subjects Protection:Federal regulations (45 CFR 46) require that
applications and proposals involving human subjects must be evaluated with
reference to the risks to the subjects, the adequacy of protection against
these risks, the potential benefits of the research to the subjects and others,
and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and Safety Monitoring Plan:Data and safety monitoring is required for all types
of clinical trials, including physiologic toxicity and dose-finding studies
(phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative
trials (Phase III). Monitoring should be commensurate with risk. The
establishment of data and safety monitoring boards (DSMBs) is required for
multi-site clinical trials involving interventions that entail potential risks
to the participants (NIH Policy for Data and Safety Monitoring, NIH Guide
for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Sharing Research Data:Investigators submitting an NIH application seeking
$500,000 or more in direct costs in any single year are expected to include a
plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).

Investigators should seek guidance from their
institutions, on issues related to institutional policies and local IRB rules,
as well as local, State and Federal laws and regulations, including the Privacy
Rule. Reviewers will consider the data sharing plan but will not factor the
plan into the determination of the scientific merit or the impact/priority score.

Access to Research Data through
the Freedom of Information Act:The Office of Management and Budget (OMB) Circular
A-110 has been revised to provide access to research data through the Freedom
of Information Act (FOIA) under some circumstances. Data that are (1) first
produced in a project that is supported in whole or in part with Federal funds
and (2) cited publicly and officially by a Federal agency in support of an
action that has the force and effect of law (i.e., a regulation) may be
accessed through FOIA. It is important for applicants to understand the basic
scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.
Applicants may wish to place data collected under this funding opportunity in a
public archive, which can provide protections for the data and manage the
distribution for an indefinite period of time. If so, the application should
include a description of the archiving plan in the study design and include
information about this in the budget justification section of the application.
In addition, applicants should think about how to structure informed consent
statements and other human subjects procedures given the potential for wider
use of data collected under this award.

Sharing of Model Organisms:NIH is committed to support efforts that encourage
sharing of important research resources including the sharing of model organisms
for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm).
At the same time the NIH recognizes the rights of grantees and contractors to elect
and retain title to subject inventions developed with Federal funding pursuant
to the Bayh Dole Act (see the NIH Grants Policy Statement).
Beginning October 1, 2004, all investigators submitting an NIH application or
contract proposal are expected to include in the application/proposal a
description of a specific plan for sharing and distributing unique model
organism research resources generated using NIH funding or state why such
sharing is restricted or not possible. This will permit other researchers to
benefit from the resources developed with public funding. The inclusion of a
model organism sharing plan is not subject to a cost threshold in any year and
is expected to be included in all applications where the development of model
organisms is anticipated.

Inclusion of Women, Minorities, and Children:It is the policy of the NIH that women and members of
minority groups and their sub-populations must be included in all NIH-supported
clinical research projects unless a clear and compelling justification is
provided indicating that inclusion is inappropriate with respect to the health
of the subjects or the purpose of the research. This policy results from the
NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All
investigators proposing clinical research should read the "NIH Guidelines
for Inclusion of Women and Minorities as Subjects in Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html);
a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.
The amended policy incorporates: the use of an NIH definition of clinical
research; updated racial and ethnic categories in compliance with the new OMB
standards; clarification of language governing NIH-defined Phase III clinical
trials consistent with the SF424 (R&R) application; and updated roles and
responsibilities of NIH staff and the extramural community. The policy
continues to require for all NIH-defined Phase III clinical trials that: a) all
applications or proposals and/or protocols must provide a description of plans
to conduct analyses, as appropriate, to address differences by sex/gender
and/or racial/ethnic groups, including subgroups if applicable; and b)
investigators must report annual accrual and progress in conducting analyses,
as appropriate, by sex/gender and/or racial/ethnic group differences.

Inclusion of Children as Participants in Clinical
Research:The NIH maintains a policy that children (i.e.,
individuals under the age of 21) must be included in all clinical research,
conducted or supported by the NIH, unless there are scientific and ethical
reasons not to include them.

Required Education on the Protection of Human
Subject Participants:NIH policy requires education on the protection of
human subject participants for all investigators submitting NIH applications
for research involving human subjects and individuals designated as key
personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

NIH Public Access Policy:NIH-funded investigators are requested to submit to
the NIH manuscript submission (NIHMS) system (http://www.nihms.nih.gov) at
PubMed Central (PMC) an electronic version of the author's final manuscript
upon acceptance for publication, resulting from research supported in whole or
in part with direct costs from NIH. The author's final manuscript is defined as
the final version accepted for journal publication, and includes all
modifications from the publishing peer review process.

NIH is requesting that authors submit manuscripts
resulting from 1) currently funded NIH research projects or 2) previously
supported NIH research projects if they are accepted for publication on or
after May 2, 2005. The NIH Public Access Policy applies to all research grant
and career development award mechanisms, cooperative agreements, contracts,
Institutional and Individual Ruth L. Kirschstein National Research Service
Awards, as well as NIH intramural research studies. The Policy applies to
peer-reviewed, original research publications that have been supported in whole
or in part with direct costs from NIH, but it does not apply to book chapters,
editorials, reviews, or conference proceedings. Publications resulting from
non-NIH-supported research projects should not be submitted.

For more information about the Policy or the
submission process, please visit the NIH Public Access Policy Web site at http://publicaccess.nih.gov/
and view the Policy or other Resources and Tools, including the Authors' Manual.

Standards for Privacy of Individually Identifiable
Health Information:The Department of Health and Human Services (HHS)
issued final modification to the "Standards for Privacy of Individually
Identifiable Health Information", the "Privacy Rule", on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance
Portability and Accountability Act (HIPAA) of 1996 that governs the protection
of individually identifiable health information, and is administered and
enforced by the HHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of
the Privacy Rule reside with the researcher and his/her institution. The OCR
website (http://www.hhs.gov/ocr/)
provides information on the Privacy Rule, including a complete Regulation Text
and a set of decision tools on "Am I a covered entity?" Information
on the impact of the HIPAA Privacy Rule on NIH processes involving the review,
funding, and progress monitoring of grants, cooperative agreements, and
research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding
must be self-contained within specified page limitations. For publications
listed in the appendix and/or Progress report, internet addresses (URLs) must be used for publicly accessible on-line journal articles. Unless
otherwise specified in this solicitation, Internet addresses (URLs)
should not be used to provide any other information necessary for
the review because reviewers are under no obligation to view the Internet
sites. Furthermore, we caution reviewers that their anonymity may be
compromised when they directly access an Internet site.

Healthy People
2010:The Public Health Service (PHS) is committed to
achieving the health promotion and disease prevention objectives of
"Healthy People 2010," a PHS-led national activity for setting
priority areas. This FOA is related to one or more of the priority areas.
Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

Authority and Regulations:
This program is described in the Catalog of Federal Domestic Assistance and is not subject to
the intergovernmental review requirements of Executive Order 12372 or Health
Systems Agency review. Awards are made under the authorization of Sections 301
and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and
under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92. All awards
are subject to the terms and conditions, cost principles, and other
considerations described in the NIH Grants Policy Statement.

The PHS strongly encourages all grant recipients to
provide a smoke-free workplace and discourage the use of all tobacco products.
In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits
smoking in certain facilities (or in some cases, any portion of a facility) in
which regular or routine education, library, day care, health care, or early
childhood development services are provided to children. This is consistent
with the PHS mission to protect and advance the physical and mental health of
the American people.

Loan Repayment Programs:NIH encourages applications for educational loan
repayment from qualified health professionals who have made a commitment to
pursue a research career involving clinical, pediatric, contraception,
infertility, and health disparities related areas. The LRP is an important
component of NIH's efforts to recruit and retain the next generation of
researchers by providing the means for developing a research career unfettered
by the burden of student loan debt. Note that an NIH grant is not required for
eligibility and concurrent career award and LRP applications are encouraged.
The periods of career award and LRP award may overlap providing the LRP
recipient with the required commitment of time and effort, as LRP awardees must
commit at least 50% of their time (at least 20 hours per week based on a 40
hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov.